Abstract/Summary Cutaneous wounds create significant health problems for Veterans, including wartime trauma, diabetic foot ulcers, pressure ulcers, and pathological scar formation. We aim to devise novel methods to stimulate self- repair mechanisms and to promote scar-less wound healing/full tissue regeneration in humans. We use a combination of loss-of-function mouse genetics, parabiosis (where the circulatory systems of two mice are surgically connected), mass cytometry, flow cytometry, genomics, lineage tracing, and molecular biology to study ear tissue regeneration in mice. Our prior work and current preliminary data demonstrate that in two different physiologic contexts, skin-secreted SDF1 regulates the switch between scar formation and tissue regeneration. In Aim 1, we will study how SDF1 promotes scarring and fibrosis. The canonical receptor for SDF1 is CXCR4. After injury, we hypothesize that skin-secreted SDF1 recruits CXCR4+ immune cells, which produce paracrine factors that induce fibroblasts to form fibrous tissue and scar. Recruited cell types will be defined and functionally tested. In Aim 2, we translate our findings directly into humans. While pathologic scar formation (keloids and hypertrophic scars) is more common in certain ethnicities, the genetic basis of keloid formation remains unknown. We hypothesize that increased SDF1 promotes formation of human pathologic scars. Indeed, human keloid tissue contains higher amounts of SDF1. We propose to identify single nucleotide polymorphisms in the SDF1 gene of keloid-prone and control patients. Identified polymorphisms will be introduced and functionally tested in an ex vivo human skin organoid system. This proposal seeks to understand how SDF1 regulates wound healing and tissue regeneration and to decipher the genetic basis for pathologic scar formation in humans.